Interaction of β-lactam carbenes with 3,6-diphenyltetrazines: a five-step cascade reaction for the direct construction of indeno[2,1-b]pyrrol-2-ones

A study of the nucleophilic addition of β-lactam carbenes to 3,6-diphenyltetrazines is reported. Instead of the formation of pyrazole derivatives like most reactions between nucleophilic or ambiphilic carbenes and 3,6-disubstituted tetrazines, β-lactam carbenes reacted with 3,6-diphenyltetrazines to produce indeno[2,1-b]pyrrol-2-ones in good yields. The reaction proceeds most probably through a five-step cascade process. This work has not only provided a one-pot operation for the efficient construction of mutisubstituted indeno[2,1-b]pyrrol-2-ones but also revealed the nucleophilicity of β-lactam carbenes.     

Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent

A comprehensive study on the gas-phase alkaline hydrolysis of cephalosporins by using the semiempirical AM1 method was carried out. Cephalothin was the model compound used on account of the presence of a good leaving group at C(3′). According to the results obtained, the hydrolysis process takes place via a twostep reaction mechanism that involves the formation of an intermediate with a fully open β-lactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the β-lactam carbonyl group of cephalosporins containing a good leaving group at C(3′). On the other hand, the alternative mechanism involving hydrolysis of the ester function in the side chain at 3′ and subsequent hydrolysis of the resulting β-lactam yieds essentially the corresponding enamine. The presence of a first solvation layer consisting of five water molecules showed that, even though some potential barriers are slightly increased, the mechanism involved is identical to that of the gas-phase hydrolysis of this antibiotic. © John Wiley & Sons, Inc.     

Quinolactacin Biosynthesis Involves Non-Ribosomal-Peptide-Synthetase-Catalyzed Dieckmann Condensation to Form the Quinolone-γ-lactam Hybrid

Quinolactacins are novel fungal alkaloids that feature a quinolone-γ-lactam hybrid, which is a potential pharmacophore for the treatment of cancer and Alzheimer's disease. Herein, we report the identification of the quinolactacin A2 biosynthetic gene cluster and elucidate the enzymatic basis for the formation of the quinolone-γ-lactam structure. We reveal an unusual β-keto acid (N-methyl-2-aminobenzoylacetate) precursor that is derived from the primary metabolite l -kynurenine via methylation, oxidative decarboxylation, and amide hydrolysis reactions. In vitro assays reveal two single-module non-ribosomal peptide synthetases (NRPs) that incorporate the β-keto acid and l -isoleucine, followed by Dieckmann condensation, to form the quinolone-γ-lactam. Notably, the bioconversion from l -kynurenine to the β-keto acid is a unique strategy employed by nature to decouple R*-domain-containing NRPS from the polyketide synthase (PKS) machinery, expanding the paradigm for the biosynthesis of quinolone-γ-lactam natural products via Dieckmann condensation.     

Mechanism of Metallo-β-Lactamase Inhibition by Oxacephalosporin Antibiotic

Metallo-β-lactamases is a family of bacterial zinc-dependent enzymes that hydrolyze β-lactam antibiotics and are responsible for the bacterial resistance to them. As a result of the reaction, the slowly hydrolyzed substrate moxalactam undergoes not only chemical transformations in the structure of the β-lactam ring but a negatively charged fragment is also released on the periphery of the molecule, resulting in the formation of an intermediate firmly bound to the active site. In the paper, we present the results of the calculations of the mechanism of this process by a combined quantum mechanics/molecular mechanics approach.     

Theoretical study of ester enolate–imine condensation route to β-lactams

The condensation reaction of the enolate of methyl acetate with formaldimine to afford a β-lactam was studied using the MP2-FC/6-31+G* level of theory taking into account the electrostatic effect of the solvent by means of a self-consistent reaction field continuum model. The reaction is a stepwise process with three main steps: the formation of the C3(SINGLE BOND)C4 bond, the closure of the β-lactam ring, and the elimination of the methoxide ion. The formation of the C3(SINGLE BOND)C4 bond is rate determining and according to our calculations is not a reversible step. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1826–1833, 1998     

ABOUT THE REACTION OF 2,3-DIBROMO-2-METHYL-N-(1-ADAMANTYL)-PROPANAMIDE WITH SODIUM TERT-BUTOXIDE. A COMPETITION EXPERIMENT

2,3-Dibromo-2-methyl-N-(1-adamantyl)propanamide (4), a precursor equally suited for the preparation of an α-lactam and a β-lactam, upon treatment with sodium tert-butoxide ether gives no α-lactam (5), but an excellent yield of the isomeric β-lactam, 1-(1-adamantyl)-3-bromo-3-methylazetidinone (6) as the only product. Repeating the experiment using a large excess of sodium tert-butoxide still leads to β-lactam 6 in 76.1% yield, but now accompanied by its dehydrobrominated derivative, β-lactam 7, in 17.4% yield, and no trace of α-lactam 5     

α-Unsaturated 3-Amino-1-carboxymethyl-β-lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment

Innovative monocyclic β-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high β-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-β-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central β-lactam ring. The present study discloses a 12-step synthesis of ten α-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced β-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased β-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the β-lactam C4-position. The significance of α-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative β-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic β-lactams as eligible PBP or β-lactamase inhibitors.     

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

The degradation of cefaclor ( 1 ), an oral cephalosporin antibiotic, was studied at 37° in a neutral aqueous medium by HPLC and ¹H-NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7-side-chain NH₂ group on the β-lactam moiety to give a piperazine-2,5-dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis- 11 from 1 involves the contraction from a six-membered cephem ring to a five-membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the Cl-atom from 3-chloro-3-cephem is a general reaction subsequent to β-lactam ring opening.     

Design and stereoselective synthesis of novel β-lactone and β-lactams as potent anticancer agents on breast cancer cells

To produce a novel class of anticancer compounds, an efficient method for synthesizing novel β-lactone and β-lactam frameworks was developed based on the reaction of a new ketene with C=O and C=N bonds. Functionalized 2-azetidinones were efficiently synthesized by employing 2,4-dichlorophenoxylketene, which was generated in situ. The reaction of the ketene with aldehydes was not successful and in all cases except for 4-nitrobenzaldehyde, a rearranged dimer of the ketene was obtained as a lactone. Anticancer cellular activity of all new β-lactams and lactones on breast cancer cells was studied. All new synthesized compounds exhibited potential anticancer activity which may guarantee their future application in moderate chemotherapy.     

A new convenient method for β-lactam formation from β-amino acids using bis(5′-nitro-2′-pyridyl) 2,2,2-trichloroethyl phosphate

Bis(5′nitro-2′-pyridyl) 2,2,2-trichloroethyl phosphate is found to be a new efficient Condensing agent for β-lactam formation from β-amino acids in acetonitrile.     

A C-N insertion of β-lactam to benzyne: unusual formation of acridone

Intermolecular insertion of benzyne into the C-N bond of a β-lactam is described. This σ-insertion is followed by ring expansion that produces dihydroquinolinone, which rapidly reacts with an additional benzyne unit to afford an acridone through intramolecular C-C bond formation to the carbonyl group and rapid elimination of ethylene.     

Toward the total synthesis of ansalactam A

Ansalactam A is a recently isolated ansa macrolide containing a spiro-γ-lactam functionality that is structurally distinct from other members of the ansa macrolide family. Herein, we describe synthetic studies toward ansalactam A. A route has been developed for the synthesis of a model system featuring a xanthate, which constitutes a direct precursor for the projected radical cyclization step aimed at the formation of the spiro-γ-lactam moiety of ansalactam A. In this context, a new practical method for the removal of an Evans auxiliary attached to sterically encumbered substrates was developed. The utilization of β-lactones as an acylation reagent, an alternative to commonly used amide coupling reactions, is described.     

New Methods for β-Lactam Formation from β-Amino Acids Using (C6H5)3P/CC14 and (C6H5)3P/NBS

Triphenylphosphine/carbon tetrachloride and triphenyl-phosphine/N-bromosuccinimide were found to be very effective for β-lactam formation from β-amino acids in acetonitrile.     

Biosensor analysis of penicillin G in milk based on the inhibition of carboxypeptidase activity

The β-lactam antibiotics, including penicillins, are the most important antimicrobial substances used for mastitis treatment. Consequently, this is also the most frequently occurring type of antibiotic residues in milk. Today, in addition to the traditional microbial inhibitor tests, rapid and sensitive receptor and immunoassays are used in residue control. Due to the limitations in throughput capacity of these tests, recent applications of automated biosensor technology in food analysis are of great interest.A surface plasmon resonance (SPR)-based biosensor (Biacore) was used to design an inhibition assay to detect β-lactam antibiotics in milk. A microbial receptor protein with carboxypeptidase activity was used as detection molecule. One advantage of using this receptor protein over antibodies that are more commonly used is that only the active, intact β-lactam structure is recognized, whereas most antibodies detect both active and inactive forms. In the presence of β-lactam antibiotics the formation of a stable complex between receptor protein and antibiotic inhibits the enzymatic activity of the protein. The decrease in enzymatic activity was measured using an antibody against the degraded substrate and penicillin G in milk samples was quantitatively determined. The limit of detection of the assay for penicillin G was determined to 2.6 μg kg⁻¹ for antibiotic-free producer milk, which is below the European maximum residue limit (MRL) of 4 μg kg⁻¹. The coefficient of variation at 4 μg kg⁻¹ penicillin G, ranged between 7.3 and 16% on three different days.     

New -lactam antibiotics. Preparation of 7-aminocephalocillanic acid

‘7-aminocephalocillanic acid’ 1 , an intermediate for the preparation of new β-lactam antibiotics was prepared by transforming the β-lactam carbinol 2a to the phosphorane 9a through several steps. Oxydation of 9a with DMSO/Ac₂O led directly to the cyclized ester 11a , which has been converted into 1 by known methods.     

Stereospecific synthesis and antibiotic activity of some cephalosporin analogs

The strategy used for the stereospecific synthesis of benzofused octams as cepham analogs was the conversion of a 3,4-dihydrothioisocarbostyril to a thioimidate, cycloaddition reaction to form a fused β-lactam and subsequent removal of the alkylthio group by Raney nickel hydrogenolysis. Using azidoacetyl chloride for forming the β-lactam and following known procedures, an amido side chain was generated. Two of the carba analogs of cephalosporin so produced showed low levels of antibacterial activity against a number of gram positive and gram negative organisms.     

Stereospecific novel glycosylation of hydroxy β-lactams via iodine-catalyzed reaction: a new method for optical resolution

Glycosylation of racemic and optically active α-hydroxy β-lactams by reaction with a few glycal derivatives in the presence of catalytic amounts of iodine has provided stereospecific formation of α-glycosides. This method has been extended for the preparation of optically active hydroxy β-lactams in excellent yields. The stereochemistry and nature of the glycals as well as the stereochemistry of the β-lactam ring has a profound influence for effective glycosylation.     

A convenient synthesis of α-amino-β-lactams

A safe and convenient method is described for the synthesis of α-amido-β-lactams starting with glycine and an azomethine. The amino group of glycine is protected by reaction with a β-dicarbonyl compound following the method of Dane etal. and the carboxyl group is activated through the formation of a mixed anhydride or an active ester. Condensation between these glycine derivatives and acyclic or cyclic imino compounds (including thioimidates) in presence of triethylamine leads to stereospecific synthesis of 3-(β-carbonyl-vinylamino)-2-azetidinones in 40–60% yield. The vinylamino side chain can be hydrolyzed under mild acid conditions to form 3-amino-2-azetidinones which can be acylated to α-amido-β-lactams. Alternatively, the vinylamino side chain can be converted to an amido side chain by ozonolysis. The molecular parameters of a 3-(β-carbonyl-vinylamino)-2-azetidinone were determined by X-ray crystallography. Usefulness of this α-amido-β-lactam synthesis is illustrated by the preparation of isotopelabeled β-lactams and intermediates for some β-lactam antibiotics.     

Synthesis of highly functionalized β-lactam substituted pyrroloisoquinoline and indolizinoindole system by sequential intermolecular 1,3-dipolar cycloaddition reaction and Pictet-Spengler cyclization

Synthesis of novel pyrroloisoquinoline and indolizinoindole derivatives with β-lactam unit has been achieved by sequential intermolecular 1,3-dipolar cycloaddition reaction and Pictet-Spengler cyclization. The azomethine ylide derived from β-lactam imine of α-amino ester in the presence of silver acetate reacted with nitrostyrenes to give pyrrolidinyl β-lactam, which underwent Pictet-Spengler cyclization in presence of trifluoroacetic acid to give pyrroloisoquinolines and indolizinoindoles.     

β-Lactams from tetrahydro-1,2-oxazine-3,6-diones

The photolysis and thermolysis of (4) and the photolysis of (5) result in the formation of the β-lactams (6) and (7); a mechanism which involves 1,4-diradicals is proposed and the possible relationship of this process to the biosynthesis of the β-lactam ring of isopenicillin N is discussed.